Novel Matrix Stiffness-regulated Genes in Lymphangiogenesis and Angiogenesis

Descripción del proyecto

El río de la vida: la formación de vasos sanguíneos y linfáticos en la matriz extracelular

La sangre y la linfa circulan por el cuerpo en vasos sanguíneos y linfáticos que forman redes complejas por todos los tejidos. La sangre transporta gases, nutrientes y residuos metabólicos. El sistema linfático drena el exceso de líquidos y proteínas de los tejidos del cuerpo y los devuelve al torrente sanguíneo, evitando así la hinchazón. Unos investigadores han demostrado recientemente que la rigidez de la matriz extracelular (MEC) afecta a la formación de nuevos vasos linfáticos. Con el apoyo del programa Acciones Marie Skłodowska-Curie, el proyecto STRomA está investigando el papel de la rigidez de la MEC en la formación de nuevos capilares y vasos linfáticos, con el objetivo de destacar las diferencias y similitudes mecánicas.

Objetivo

Endothelial cells (ECs) recognize and respond to mechanical forces through their cell-cell and cell-matrix adhesions and translate physical stimuli into biological responses in a process called mechanotransduction. The composition and mechanical properties of the extracellular matrix (ECM) differ across the vascular tree, in its surrounding tissues and in development and diseases, such as edema formation. I have recently shown for the first time that ECM stiffness fundamentally controls lymphangiogenesis. I hypothesize that changes in ECM stiffness are a key regulatory mechanism of angiogenic processes in development and disease. A comprehensive analysis of novel ECM stiffness-regulated genes is pivotal to understand these processes integrally. In a preliminary study, I have performed differential RNA sequencing of blood (B) and lymphatic (L) ECs cultured on soft and stiff matrices. 3200 genes were regulated similarly in BECs and LECs in response to changes in matrix stiffness. Interestingly, the same number of genes was differently regulated. In the next two years, I will study the role of selected genes in lymphangiogenesis and angiogenesis in vitro and in transgenic mouse models with state-of-the-art microscope and live imaging techniques. First, I will analyze an actin-regulating protein family that is significantly regulated by matrix stiffness in both, BEC and LECs, suggesting a more general role in lymphangiogenesis and angiogenesis by regulating cytoskeletal dynamics. Second, I will study a molecule, which is involved in intracellular cGMP signaling and is predominantly regulated in LECs, suggesting a more specific role in lymphangiogenesis. Last, I will generate an in vitro fluorescent stiffness sensor to live-visualize changes in stiffness inside the EC. Ultimately, the proposed action can provide novel targets to modulate lymph and blood vessel formation with implications for edema treatment and will support me to become an independent group leader.